Translational Pathway for Ventricular Assist Devices
Unmet Clinical Needs
Francis D. Pagani, MD
Sir Magdi Yacoub, MD
Use of evidence-based medical therapy, advanced pacemakers, and implantable defibrillators has changed prognosis in heart failure (HF) dramatically. However, between 0.5% and 5% of patients respond poorly to standard therapy, leading to their developing chronic advanced HF. Data from the United States suggest that 250,000 to 300,000 patients younger than 75 years suffer from advanced systolic HF (defined as New York Heart Association class IIIb-IV) (1). Extrapolating these figures to Europe would equate to a population of 500,000 patients in the European Union. Prognosis in advanced HF is grave, with a 1-year mortality in ambulatory class III-IV patients >25% and exceeding 50% in class IV patients.
While palliative care is the treatment of choice for patients of advanced age or patients burdened with significant comorbidity, advanced therapies, such as heart transplantation or a left ventricular assist device (LVAD), should be considered for others. Heart transplantation is an excellent treatment option for many patients, but suitable donor availability is extremely limited. Implantable LVADs have been used for decades in very advanced HF or cardiogenic shock primarily as a bridge to heart transplantation. Improvements in technology, especially the advent of smaller, durable continuous-flow pumps, coupled with a shortage of donor hearts for transplantation, have led to use of LVADs in a much broader population of patients in the last 10 years (1).
Over the past 20 years, ventricular assist devices (VADs) have become a standard therapeutic option for treating end-stage HF patients. With the evolution of the therapy, other potential clinical applications of VADs beyond end-stage HF could be considered. In 2008, the National Heart, Lung, and Blood Institute (NHLBI) convened a working group of experts on heart failure cardiology, cardiac surgery, clinical trial design, medical ethics, and regulatory affairs to advise the NHLBI on the treatment of advanced heart failure using VADs and how therapy for heart failure may be best advanced by clinical trials involving VADs (2). The working group reached consensus that:
— an unmet clinical need currently exists for HF patients who remain symptomatic with a depressed ejection fraction despite conventional medical therapy;
— equipoise exists for designing a clinical trial with circulatory assist devices in less ill patients with the current generation of VADs; and
— a scientifically rigorous trial can be designed to address the clinical use of VADs in less ill patients.
Out of this effort, the REVIVE-IT (Randomized Evaluation of VAD Intervention Before Inotrope Therapy) clinical trial was realized. The specific objective of REVIVE-IT was to compare LVAD therapy with optimal medical management in patients with less advanced HF than current LVAD indications to determine if wider application of permanent LVAD use would be associated with improved survival, quality of life, or functional capacity. REVIVE-IT represented an extraordinary effort to provide data from a randomized clinical trial to inform clinicians, scientists, industry, and regulatory agencies about the efficacy and safety of LVAD therapy in a population with less advanced HF. Despite significant support from the medical community, industry, and governmental agencies, REVIVE-IT failed to accomplish its goal and was terminated early due to insufficient enrollment as a consequence of the concern for adverse events in the study device, the HeartMate II (3).
Whether a trial of LVAD therapy in patients with less advanced HF will ever be completed in the future is unknown. There is some debate as to whether a randomized clinical trial (RCT) studying LVAD therapy in patients with less advanced HF is necessary. Some thought experts assert that the data necessary to offer LVAD therapy to patients with less advanced HF can be obtained from registry data or non-randomized observations trials. More recently, data were reported from the ROADMAP (Risk Assessment and Comparative Effectiveness of Left Ventricular Assist Device and Medical Management in Ambulatory Heart Failure Patients) study, a multicenter, nonrandomized observational study evaluating LVAD therapy in ambulatory non-inotrope-dependent patients compared with optimal medical management (OMM) (4). ROADMAP demonstrated improved survival free from urgent transplant or subsequent LVAD placement for patients assigned to LVAD therapy compared with OMM (80 ± 4% vs. 63 ± 5%; p = 0.022) when the data were analyzed according to initial treatment assignment.
However, this outcome was completely driven by the need for LVADs in 22% of the OMM arm. Moreover, overall survival free of urgent transplant at 1 year (when change of therapy from OMM to LVAD was removed from the composite outcome) was not statistically different for LVAD compared with OMM (82 ± 4% vs. 81 ± 4%; p = 0.931), with very similar risks for both death within 1 year (22% for OMM vs. 20% for LVAD) and urgent transplant (0% for OMM vs. 2% for LVAD). Adverse events were higher in patients with LVADs (1.89 events per patient-year [EPPY], primarily driven by bleeding [1.22 EPPY]) than in patients with OMM (0.83 EPPY, mainly worsening HF [0.68 EPPY]). More LVAD recipients required subsequent hospitalization, but hospitalization was common in both groups (80% LVAD vs. 62% OMM; p < 0.001). It is unknown whether REVIVE-IT would have demonstrated similar findings. However, the results of ROADMAP clearly demonstrate the potential for bias in the study population without randomization and speak to the need for an RCT to more definitively evaluate the use of LVAD therapy in a population with less advanced HF.
Improving technology and recent results from the MOMENTUM 3 clinical trial demonstrate an important reduction in risk of pump thrombosis and stroke associated with VAD therapy (5.6). Whether, these improvements in technology are significant enough to result in greater adoption of VAD therapy in ambulatory, non-inotrope dependent patients remains to be seen. Clearly, with the limitations in heart transplantation to address the needs of the increasing HF population, VAD technology needs to continue to improve to ensure its utility in a less ill population of patients with advanced heart failure.
- Miller LW. Is left ventricular assist device therapy underutilized in the treatment of heart failure? Left ventricular assist devices are underutilized. Circulation. 2011;123:1552-8.
- Baldwin JT, Mann DL. NHLBI’s program for VAD therapy for moderately advanced heart failure: the REVIVE-IT pilot trial. J Card Fail. 2010;16:855-8.
- Pagani FD, Aaronson KD, Kormos R, et al. The NHLBI REVIVE-IT study: Understanding its discontinuation in the context of current left ventricular assist device therapy. J Heart Lung Transplant. 2016;35:1277-83.
- Estep JD, Starling RC, Horstmanshof DA, et al. Risk assessment and comparative effectiveness of left ventricular assist device and medical management in ambulatory heart failure patients. J Am Coll Cardiol. 2015;66:1747-61.
- Mehra MR, Naka Y, Uriel N, et al. A fully magnetically levitated circulatory pump for advanced heart failure. N Engl J Med. 2017;376:440-50.
- Mehra MR, Goldstein DJ, Uriel N, et al. Two-year outcomes with a magnetically levitated cardiac pump in heart failure. N Engl J Med. 2018;378:1386-95.